Endovascular stents have become increasingly important in medical procedures to restore the function of bodily lumens. With generally open tubular structures, the stents typically have apertured or lattice-like walls of a metallic or polymeric base, and can be either balloon expandable or self-expanding. A stent is typically deployed by mounting the stent on a balloon portion of a balloon catheter, positioning the stent in a body lumen, and expanding the stent by inflating the balloon. The balloon is then deflated and removed, leaving the stent in place. Stents help reduce the probability and degree of vessel blockage from restenosis.
An increasing number of stents for treating vascular conditions are being coated with protective materials and bioactive drugs. A variety of stent coatings and compositions have been proposed to provide localized therapeutic pharmacological agents and treatment of a vessel at the site being supported by the stent. Stent coatings with various families of drug polymer chemistries have been used to increase the effectiveness of stenting procedures and to control drug-elution properties. For example, polymeric coatings can be made from polyurethane, polyester, polylactic acid, polyamino acid, polyorthoester, and polyphosphate ester. Examples of drug or bioactive agents include antirestonotic and anti-inflammatory compounds.
Medical research indicates a greater effectiveness of vascular stents when stents are coated with pharmaceutical drugs that help prevent or treat medical conditions such as restenosis and thrombosis. These drugs may be released from a coating while in the body, delivering their patent effects at the site where they are most needed. The localized levels of the medications can be elevated, and are therefore potentially more effective than orally or intravenously delivered drugs. Furthermore, drugs released from tailored stent coatings can have controlled, timed-release qualities, eluting their bioactive agents over hours, weeks or even months. Stent coatings typically have a drug or active agent, which has been dissolved or dispersed throughout the polymeric material and physically constrained within the polymer. The sustained release of drugs generally relies upon either degradation of the polymer or diffusion through the polymer to control the elution of the compounds.
Drug polymer coatings on medical devices such as stents and catheters need to be mechanically pliant because the devices undergo significant flexion or expansion during the delivery and deployment. A stent deployed by self-expansion or balloon expansion is accompanied by a high level of bending at portions of the stent framework, which can cause cracking, flaking, peeling, or delaminating of many candidate drug polymers when the stent diameter is increased by threefold or more during expansion. In addition, any step within the process for coating a pre-deployed stent should not cause a drug-polymer to fall off, crystallize or melt. Chudzik et al. disclose a flexible coating composition to address the need for pliancy in “Bioactive Agent Release Coating”, U.S. Pat. No. 6,344,035 issued Feb. 5, 2002. The bioactive agent or drug is in combination with a mixture of polymers such as poly(butyl methacrylate) and poly(ethylene-co-vinyl acetate). Polymers for use as stent coatings need to demonstrate characteristics of biocompatibility, good drug release as well as flexibility.
In selecting polymers for drug delivery and applying drug coatings to stents, certain criteria must be met: polymer biocompatibility, satisfactory mechanical properties such as durability and integrity during roll down and expansion of the stent, and correct release profiles for the drugs. Candidate chemistries for drug polymers may result in excessively rapid elution of an incorporated drug. When a drug is eluted too quickly, it may be ineffective and may fail to achieve the desired effect in the surrounding tissue bed. If a drug is eluted too slowly, the pharmaceutical intent may remain unfulfilled. Furthermore, incorporation of more than one drug in the same coating can result in a much faster elution rate than a second drug in the same drug polymer, making the controlled delivery of multiple drugs difficult. Even pharmaceutical compounds with nearly the same pharmaceutical effect can have dramatically different elution rates in the same coating chemistry, depending on the formation of the compounds.
Stents can be coated with a polymer or combination of a polymer and a pharmaceutical agent or drug by application techniques such as dipping, spraying, painting, and brushing. In many of the current medical device or stent coating methods, a composition of a drug and a polymer in a solvent is applied to a device to form a substantially uniform layer of drug and polymer. A common solvent for the polymers and drugs employed is usually required, and techniques have been developed to micronize the drugs into small particles so that the drugs can be suspended in the polymer solution. Micronization can be time consuming, and may result in a degradation or loss of desired therapeutic properties of the drug. A method of using micronized drugs and layering a drug-coated stent using pharmacological and polymeric agents is described by Guruwaiya et al. in U.S. Pat. No. 6,251,136 issued Jun. 26, 2001. A pharmacological agent is applied to a stent in dry, micronized form over a sticky base coating. A membrane-forming polymer, selected for its ability to allow the diffusion of the pharmacological agent therethrough, is applied over the
entire stent. More specifically, a stent, typically a metal stent, has a layer of a sticky material applied to selected surfaces of the stent. A pharmacological agent is layered on the sticky material and a membrane forming a polymer coating is applied over the pharmacological agent. The membrane is formed from a polymer that permits diffusion of the pharmacological agent over a predetermined time period.
A method of applying drug-release polymer coatings that uses solvents is described in “Method of Applying Drug-Release Coatings”, Ding et al., U.S. Pat. No. 5,980,972 issued Nov. 9, 1999. A polymer is dissolved in one solvent and a drug is dissolved or suspended in a similar or different type of solvent. The solutions are applied either sequentially or simultaneously onto the devices by spraying or dipping to form a substantially homogenous composite layer of the polymer and the biologically active material.
Many of the drug-coated stents in recent years have been sprayed with rather than dipped in a drug-polymer solution. Spray coating, a currently preferred method for coating stents, can result in a significant amount of spray material lost during the process and when expensive drugs are used in these coatings, the use of spray coating may be costly.
Dip coating was used with early stents and other medical-device designs that were of relatively open construction fabricated from wires or from ribbons. Dipped coatings with relatively low coating weights, for example, coatings with about 4% polymer, were used with some occurrences of bridging or webbing of the coating in the open spaces or slots between the structural members of the device. Such coating methods were performed by manually dipping the stent in a liquid, and then removing the stent and drying it. The dipping process requires care to avoid excess liquid on the stent framework or inconsistent drying of the liquid, otherwise the apertures can become blocked unnecessarily. Applying a thick coating tends to exacerbate webbing and bridging problems, and increasing the solids content of the coating solution also increases webbing and bridging between the struts. Any coating method needs to avoid webbing, as well as control the weight and thickness of a coating.
Problems of webbing and having excess coating material on stent struts are recognized by those skilled in the art of manufacturing stents. For example, a manual-dipping process step that blows excess material off the open framework of a tubular stent is disclosed in “Coating” by Taylor et al., U.S. Pat. No. 6,214,115 issued Apr. 10, 2001. The process addresses the problems of inconsistent drying and blockage of openings. Another dipping process that addresses the issues of blockage and bridging between the stent struts is disclosed by Hossainy et al. in “Process for Coating Stents”, U.S. Pat. No. 6,153,252 issued Nov. 28, 2000. Flow or movement of the coating fluid through the openings in the perforated medical device is used to avoid the formation of blockages or bridges. The flow system may use a perforated manifold inserted in the stent to circulate the coating fluid, or may place the stent on a mandrel or in a small tube that is moved relative to the stent during the coating process.
Newer stents that are of less open construction, such as catheter-deployed, self-expanding stents are more difficult to coat evenly using a dipping method. Nevertheless, one advantage of dip coating is the ability to process a greater number of stents in a more efficient manufacturing process. A stent with a single coating having at least one therapeutic agent is described by Sirhan and Yan in “Delivery or Therapeutic Capable Agents”, U.S. Patent Application No. 20020082679 published Jun. 27, 2002. Barry and others describe another polymer composition that can be used for delivering substantially water-insoluble drugs in “Loading and Release of Water-insoluble Drugs”, U.S. Pat. No. 6,306,166 issued Oct. 23, 2001. A medical device is coated with one or more layers of a volatile organic solution comprising a polyvinyl aromatic polymer and an antineoplastic chemotherapy drug such as paclitaxel. In the descriptions of the aforementioned coatings, dipping is given as one of the methods for applying the drug-polymer coating to the device, although the disclosures do not address the potential problem of webbing or bridging in the open areas of stent structures, particularly when multiple coats are applied.
Jayaraman proposes a solution to the webbing or bridging issue in “Process for Coating a Surface of a Stent”, U.S. Pat. No. 6,517,889 issued Feb. 11, 2003. The coating process includes inserting a thread through the lumen of the stent and producing relative motion between the stent and the thread to remove coating material located within the openings of the stent.
Multiple dips can be used to build up the weight and thickness of the coating, but each subsequent dip may affect the coating already deposited. A coating can re-dissolve in a second coating solution, causing some loss of the first layer of coating. Also, applications of multiple dip coats from low concentration solutions can have the effect of reaching a limiting loading level as equilibrium is reached between the solution concentration and the amount of coating with or without a pharmaceutical agent. One such method that applies a plurality of relatively thin coatings on an open-lattice stent is disclosed in “Drug Release Stent Coating”, Ding et al., U.S. Pat. No. 6,358,556 issued Mar. 19, 2002. The stents are coated by dipping or preferably spraying the stent with a solvent mixture of uncured polymeric silicone material with a crosslinker and a finely divided biologically active species. The method includes a step for sterilizing with an inert argon gas plasma and exposure to gamma radiation. Potential problems with bridging or webbing in the lattice framework are not addressed.
Accordingly, what is needed is a more efficient manufacturing method for coating medical devices such as stents that can apply drug-polymer coatings without creating undesirable bridging or webbing. An improved process provides coatings that are well adhered and flexible, a well as controls coating properties such as thickness, porosity, and smoothness. An improved stent with one or more drug-polymer coatings maintains mechanical integrity during its deployment, provides a desired elution rate for one or more drugs, and overcomes the deficiencies and limitations described above.